1,721,121 research outputs found
Dimerization hot spots in the structure of human Hsp90
No full textHeat shock protein 90 (Hsp90) is an ubiquitous molecular chaperone responsible for the assembly and regulation of many signal transduction and regulatory client proteins. Since Hsp90 refolds, stabilizes and regulates the trafficking of many proteins responsible for uncontrolled proliferation and apoptotic resistance, including multiple protein kinases, steroid hormone receptors, mutated p53, survivin and others, this chaperone is an emerging target for the development of anticancer drugs.1,2
Hsp90 is a large and conformationally dynamic protein that undergoes dramatic conformational changes upon ATP binding and hydrolysis. Crystallography, small-angle X-ray scattering and electron microscopy techniques have revealed an underlying conformational complexity of Hsp90, which is composed by three highly dynamic domains, the N-terminal (NTD), middle (MD) and C-terminal (CTD) domains.3 Dimerization is an essential step of the Hsp90 cycle. Recently, the crystal structure of yeast Hsp90 in complex with an ATP analogue and the co-chaperone p23/Sba1 revealed the architecture of the closed and compact homodimer, providing a view of Hsp90 in the ATP-bound state, which represents an obliged conformation along the ATPase cycle.4
This work reports the results of a molecular dynamics and dimerization free energy analysis performed on the structure of a human Hsp90 homology model in the closed conformation. Decomposition of free energies on a residue basis led to the prediction of five clusters of dimerization hot spots, three of which are located in the NTD while the other two in the CTD. These residues represent valuable candidates for future mutagenesis studies and may provide new sites for the design of allosteric inhibitors
Emerging Topics in Structure-Based Virtual Screening
No full textMolecular dynamics simulations and the generation of ad hoc chemical libraries are playing an increasingly important and recognized role in structure-based virtual screening. These approaches are important for treating target flexibility and improving the drug discovery pipeline. In this article I will comment on these two topics and put them into perspective
Disegnare i farmaci al computer
No full textNon solo chimica e biologia: anche l’informatica è
diventata fondamentale per progettare e sviluppare
nuovi farmaci. Un progettista molecolare ci spiega
come, partendo da informazioni genetiche e
strutturali, il computer semplifichi e velocizzi la
ricerca di sostanze terapeutiche
Unveiling target associations for polypharmacology from analysis of crystallographic ligands in the Protein Data Bank
No full textNovel and less explored chemotypes of natural origin for the inhibition of Hsp90
No full textThe Hsp90 chaperone is a promising target for the treatment of cancer. Well known inhibitors, e.g.
geldanamycin, radicicol, novobiocin and their derivatives, have been extensively investigated and optimized
as inhibitors of Hsp90. More recently, new chemotypes of natural origin were reported to modulate Hsp90
function via various and often “non-conventional” mechanisms. This review focuses on these novel classes
of natural products whose structures have not yet been thoroughly explored for medicinal chemistry purposes.
These novel chemotypes may constitute interesting starting points for future drug discovery
campaigns
Targeting the allosteric sites of the B-Raf protein kinase through an in silico approach
No full textMolecular dynamics simulations of the structure of aldose reductase complexed with the inhibitor Tolrestat
No full textThis study reports a molecular dynamics (MD) investigation on the structure of aldose reductase (ALR2) complexed with the potent inhibitor tolrestat. The simulations predict four different orientations of tolrestat into the ALR2 binding site; these orientations have in common a strong interaction of the anionic carboxylate with Tyr48, His110, Trp111 and NADP+, but completely differ for the orientation of the aromatic portion of the inhibitor. Interestingly, the orientation in which tolrestat gives the most attractive interaction energy with the enzyme is in full accord with the x-ray crystal structure of the complex that has been reported in the literature after this work was completed. In addition, the suggestion of more than one orientation of tolrestat during MD is in agreement with recent electrospray mass spectrometry experiments on the ALR2-tolrestat complex
Rational design of dual inhibitors of Hsp90 and B-Raf as a novel pharmacological approach against melanomas
No full text
Enrichment Factor Analyses on G-Protein Coupled Receptors with Known Crystal Structure
No full textG-protein coupled receptors (GPCRs) are highly relevant drug targets. Four GPCRs with known crystal structure were analyzed with docking (AutoDock4) and postdocking (MM-PBSA) in order to evaluate the ability to recognize known antagonists from a larger database of molecular decoys and to predict correct binding modes. Moreover, implications on multitarget drug screening are put forward. The results suggest that these methods may be of interest to the growing field of GPCR structure-based virtual screening
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